Open Cervicocranial dysfunction, neuroinflammation and infection in ME/CFS compared to healthy subjects, Bragée & Bertilson [MEPRO study]

I have seen many examples where the cxa doesn't change much in flexion, as one would expect it to if everytbing was normal. I wish i could cite these examples, but they are people's private reports. But with horizontal instability it does not seem inconceivable for tje cxa to not be directly related to flexion and i have seen no evidence that it is. In most people it is smaller in flexion but i have seen examples where it did not decrease. Its true that the possibility of it being due to flexion can't be ruled out but I don't think it can be safely assumed to be due to flexion alone.

Is there some way to standardize the alignment of supine and upright (eg lining up the rest of the spine and head so one can see if the position is different ) ?

 

After writing the above I realised that I was probably overlooking the capabilities of modern 3D post-processing software, so I spoke to colleague at work who is into 3D modelling and tomography. Basically it does not matter how a sample (a human head in this case) is 'sliced' by an MRI, because once the data has been captured in enough detail, 3D graphics software can subsequently reconstruct any sort of 'slice' through the sample you might wish, irrespective of how the data capture actually did the slices.

Which means that if a skilled operator had both supine and upright 3D scans on a screen in front of them, they could move the 2D slice image of each forwards and backwards, and rotate them at will. This means they could look for some key features that could be guaranteed to not change with posture or gravity, and then manipulate the two images until those features were near-identical in both supine and upright images. I imagine such reference points could be found in the skull case itself? With such alignment, this would then eliminate any discrepancies due to misalignment.

 

Michael vanelzakker has spoken about these difficulties ans this process in his speech at the NIH conference. He would be a good person to discuss this with. He was discussing alignment in the context of studies looking for glial activation but i presume that it would be relevant to structural issues as well.

However, im unsure he would want to jpin s4ME as this debate has become heated and a little bit broader than just being purely about the science and he may want to not be seen to take a side so to speak. Still, it may be worth asking him about upright vs supine imaging and how one could do some kind of alignment to make sure the differences weren't due to head posture Chang.e

I actually think you might need a different software or process than what he used bc in his case they were trying to align the brainstems to look for non structural abnormalities, whereas with a structural abnormality you'd be looking for *misalignment* and you'd want to align *everything else*.

This is a very interesting discussion. Its not purely academic to me as I may have surgery , but I do like discussing things in which i have "skin in the game".

 

Its worth noting that while they didn't compare dynamic imaging in patients vs healthy controls, the chiari malformation patients that did not have a connective tissue disorder differed greatly in the upright imaging results, so the study did have a sort of control aand identifies statistically significant differences in dynamic imaging (which i think is notable, even if i think that they should have included healthy controls as well)

 

So i did find the PDF for this study on scihub. Where they compare three groups--people with chiari malformation I but no suspected CTD, people with chiari malformation I but also CTD, and healthy controls ! So we do have at least one study that has healthy controls. However we don't have one, that i can find, that has people with cci but no chiari compared to healthy controls.

https://thejns.org/spine/view/journals/j-neurosurg-spine/7/6/article-p601.xml
I can't upload the file due to a problem with my phone... But if you put the doi of the aforementioned study into scihub, you should get the pdf!

 

All I'm really saying is that when looking for differences between supine and upright images, it is crucial to null out any differences due to the two images not being the exact same slice through the head. My suggestion is a way to achieve that; if it's not already being done by people looking for differences, then that would seem to be a major oversight.

 

I may have used the term flexion loosely. Decrease or CXA will be due to atlanto-occipital nodding, which is a different movement from cervical flexion. You can and do perform them quite separately but most people are unaware that they do most of the time. I have seen no discussion in any of these papers of how to control for the relative effects the two movements.

Everything I have seen so far suggests to me that the changes in measurements are due to normal movements. Range of movement may be greater in hyper mobile individuals but I cannot see any evidence that it is an indication for surgery. And it seems nor can most neurosurgeons.

 

Maybe it would be useful to explain it a different way, although I think I have covered this before.

If measurements change it means the bones move in relation to each other. That movement could be in part along the normal planes of joint movement - which is what we call change in posture. It could also be in part an abnormal movement not normally allowed by the joints.

In this case we are talking of evidence for 'settling' which means the skull (occiput, basin or clivus) moving down in relation to the peg of the second cervical vertebra, C2 (the axis). The rationale for traction seems to be to pull the skull up again in relation to C2.

C2 can move on C1 and C1 can move on the occiput, so settling could hypothetically occur at either or both levels,. However, the occiput and C1, even in disease, are incompressible bones in contact. You cannot get one incompressible object to move down into another incompressible object it is in contact with. So settling is not occurring at occiput/C1.

That means that settling must be due to a movement of C2 on C1. This is possible because the tapered peg of C2 (dens) slots up inside C1 and is prevented from going higher by a ligament, not by bone. If the ligament fails then C2 can go up through C1 to get closer to the occiput.

If we are concerned about settling at C1/C2 then the only sensible measurement is between a fixed point on C1 and a fixed point on C2. Not a basion/C2dens or a basion/C1atlas measurement but a C1atlas/C2dens measurement (which is what we used twenty years ago). Moreover, it needs to be a vertical distance for settling. A horizontal distance is relevant but for other concerns.

As far as I remember the measurements being discussed in relation to sitting are not atlas/dens measurements but measurements that can be affected by normal joint movement. And my understanding was that there was no change in atlas/dens vertical measurement and that this is why there was talk of 'functional settling' which seems to mean that some measurements change as they might do with settling but that there is no actual C1atlas/C2dens settling (otherwise why call it functional?). As far as I can see this is very misleading terminology because there is no actual settling and the measurements that change are not the ones that specifically indicate settling.

I would suggest anyone interested in these operations takes this post to a neurosurgeon who does not recommend this sort of surgery and asks them if they agree that this is how things are understood by neurosurgeons in general.

 

Basically, there were four groups. People with connective tissue disorders (but no diagnosis of chiari malformation I), people with chiari malformation I but no connective tissue disorder , people with chiari malformation I and a CTD, and normal controls.

Many measurements were made while supine, upright and in traction.

I think it would be helpful for this discussion if someone would upload the actual paper here and especially the results page.

But what stood out to me was that all of the groups with CTD, their cxa in neutral was the same in supine position as the controls, but decreased 10 degrees sitting. Whereas the controls' cxa did not decrease at all. The p value was around .01 I think. There were a bunch of other measurements.

But that's notable to me because it showed that much of a difference with a group that had CTD but not necessarily any clinical signs of cci. Or-many of them had clinical picture of cci but they were not selected for that reason. So, I wonder what the picture would look like if you selected based on level of disability and clinical suspicion of cci from that cohort.
.food for thought.

 

This was posted on the Swedish campaign #MEvårdsaknas last week. I'm afraid it contains a lot of marketing, but it also raises some concerns regarding this upcoming study.

"[60] I have regained parts of my life"
https://mevardsaknas.wordpress.com/2019/12/12/60-jag-har-fatt-delar-av-mitt-liv-tillbaka/

In short:
A severely ill ME patient, also diagnosed with hEDS at the Bragée ME Center, was referred by them to Medserena Clinic in London for an upright MRI, when they suspected craniocervical instability.

After that the patient deteriorated gravely and developed severe apnea.
She was diagnosed with CCI/AAl etc, but then wasn't offered any treatment or care for this condition by the Bragée Clinic, neither was she referred somewhere where such treatment could be provided.

Bragée ME Center also told her the neck injuries/craniocervical instability was the cause of her ME.
She then fundraised money and arranged to have an operation in Spain herself



This raises some questions.
First, why are Bragée ME Center telling patients that CCI and craniocervical instability causes ME, when the study hasn't even begun, or been approved yet?

Second, it cannot be ruled out that the severe deterioration wasn't caused by the exertion of the travel, and maybe even the upright MRI itself. Still, they plan a study for other patients to go through the same thing? And don't mention any risks at all with this?
Other ME patients have been examined for and/or diagnosed with CCI, Chiari etc in Sweden, so why couldn't she?

Finally, when she's been diagnosed and is in dire need of care and treatment, they cannot provide any, nor can they refer her anywhere else. Seems like they don't have a plan for that.

In the answers to the Swedish Ethical Review Authority to the question :
8.How are additional findings handled at MRT performed in Sweden and London?

They answered :
In the usual manner, i.e. if the review of scans shows additional findings that require further investigation or treatment, the test subject is referred by us to the adequate medical care.

Well, they didn't refer this patient to adequate medical care, why?
So exactly what adequate medical care are potential study participants going to be referred to, if additional findings show up? And where?



Below is a cleaned up Google-translation of the post, bolding by me:

.

 

https://clinicaltrials.gov/ct2/show/NCT04403854

 

Merged thread

The MEPRO study

Bragée Clinics, Stockholm, Sweden
Björn Bragée, Bo C Bertilson
March 2021

Looking for people with ME/CFS diagnosis, and healthy controls.

More info:
https://www.bragee.se/nytt_mepro

 

I don't know. I'm trying to find out. Someone I know contacted the Ethical Review Authority, but they weren't able to find any applications by Bragée/Bertilson matching these study titles. It's possible that they are registered under different titles, or maybe they could be sub-studies of another study?

Will keep looking. I'll let you know when I know more.

 

It's problematic with a study with such high demands on participants. Severely ill people with ME can probably not participate, due to high demands that will induce PEM.

 

I believe it's the same study, from reading the description and seeing the timelines.
Trying to find the approved ethical application now, we'll keep you posted!

 

severe exercise-induced lethargy, pain and sleep disorders.
i hope this is an error in translation or it tells us the researchers have no clue about pem .

 

It's not a good word... "matthet" in Swedish. I agree, it doesn't describe the nature of PEM.

I'm not sure if Google Translate gives the best translation or not. Other synonyms would be lassitude, feebleness, langour, weakness, lacking in strength, feeling faint...

 

This is the MEPRO study: https://www.s4me.info/threads/craniocervical-dysfunction-neuroinflammation-and-infection-in-me-cfs-ws-healthy-controls-planned-study-bragée-clinic-sweden.12289/

It was awaiting approval for a long time, so we lost track of it. I've requested the approved application from the Swedish Ethical Review Authority, but the original application can be found in the thread above.

ETA :
Here's a translation of the research plan:
https://docs.google.com/document/d/111YVl4vxgO_Pwvd5GK2MBfncIHCnZS1wuo2IepyxABM/edit?usp=drivesdk

 

The hypothesis is that the disease in a significant proportion of patients can be explained by

traumatic and other changes in the craniocervical area, and sub hypotheses are that there are signs of neuroinflammation and/or infection in the blood and cerebrospinal fluid as well as a disturbance of so-called interoceptive signaling.
imho they are wasting resources the cervical injuries in m e patient are most likely down to incorrect diagnoses from the outset although it is still possible to receive such injuries after an m e diagnosis since falls are very common . the added bits are just to increase the chance of funding .